Published on Web 07/31/2009
Palladium-Catalyzed Regio-, Diastereo-, and Enantioselective Benzylic Allylation of 2-Substituted Pyridines Barry M. Trost* and David A. Thaisrivongs Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080 Received June 1, 2009; E-mail:
[email protected] The development of palladium-catalyzed asymmetric allylic alkylations (AAAs) continues to be a productive area of research.1 Still, there are only a few examples of such reactions that form an adjacent stereocenter diastereoselectively, and these are almost exclusively limited to enolate nucleophiles.2 This narrow substrate scope reflects the inherent challenge of simultaneously forming vicinal stereocenters selectively. After reporting a method for employing 2-methylpyridines in palladium-catalyzed AAAs,3 we wondered whether an analogous reaction with higher-order 2-substituted pyridines could be effected in a diastereo- and enantioselective fashion (Scheme 1, A). We hypothesized that, upon coordination of the pyridyl nitrogen atom with BF3, benzylic deprotonation would provide a nucleophile that would exist as a single geometric isomer because of the steric demands imposed by the Lewis acid. If such control were possible, alkylation products might be obtained with both high diastereo- and enantiocontrol.
Table 1. AAA Reactions with 2-Substituted Pyridyl Nucleophilesa
Scheme 1. Reaction Hypothesis and Initial Result
Unfortunately, when 2-ethylpyridine (1) was reacted with allylic carbonate 2 under the previously optimized conditions,3 1H NMR revealed no desired product and partial decomposition of 2 (Scheme 1, B). Replacing the tert-butyl carbonate ester with the more robust pivalate ester provided an electrophile that was completely stable to the reaction conditions, and with this substrate the desired alkylation product (3a) could be obtained in 15% yield, >19:1 dr, and 95% ee. Although the reaction conversion was low, the excellent diastero- and enantioselectivity validated our hypothesis. Disappointingly, higher yields could not be obtained by heating the reaction or by using other strong bases (e.g., LiTMP, t-BuOK, KHMDS, or n-BuLi). The breakthrough came when a single equivalent of n-BuLi was added to the nucleophilic complex generated with 3 equiv of LiHMDS; under these conditions, 3a was now isolated in 85% yield, >19:1 dr, and 94% ee. Presumably, the introduction of n-BuLi quantitatively deprotonates the equivalent of HMDS formed in the initial deprotonation event, driving the reaction to completion. Other 2-substituted pyridines that underwent reaction with cyclohex-2-enyl pivalate were identified (Table 1). A range of 2-alkyl and 2-aryl substituted pyridines performed well, as did the corresponding five-membered ring electrophile (see 3b). Large 12056
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J. AM. CHEM. SOC. 2009, 131, 12056–12057
a Yield reflects combined isolated yield of both diastereomers; dr and ee determined by 1H NMR analysis of the crude reaction mixture and chiral HPLC, respectively.
substituents generally provided the highest level of stereocontrol; for example, 2-(naphthalene-2-ylmethyl)-pyridine gave 3g in 90% yield, >19:1 dr, and 98% ee.4 Heteroaryl substitution was also tolerated (3h), as was an aryl bromide (3i), which did not undergo oxidative addition by palladium(0) or lithium-halogen exchange with n-BuLi. Finally, a nitrogen-containing stereocenter could also be established (3j).5 The relative and absolute stereochemistry of the products was assigned by analogy to 3d, which was bromocyclized to provide single crystals of the corresponding pyridinium cation suitable for X-ray diffraction (Scheme 2).6 The alkylation is sensitive to the steric nature of the nucleophile. When additional substituents were placed at either the benzylic (e.g., 2-isopropylpyridine) or homobenzylic (e.g., 2-neopentylpyridine) positions, no desired product was observed. Conversely, if the 2-pyridyl substituent is insufficiently sterically demanding for the two possible geometric configurations of the nucleophile to be adequately differentiated, the product is formed with low diastereocontrol (e.g., when 2-(methoxymethyl)pyridine was employed, the product was obtained in 78% yield but 3:2 dr). 10.1021/ja904441a CCC: $40.75 2009 American Chemical Society
COMMUNICATIONS Scheme 2. Bromocyclization of 3d
recognition, a single enantiomer of ligand is capable of converting both “matched” and “mismatched” substrate to product. Table 3. AAA Reactions with Deuterated Substrate 9
The reaction is not limited to cyclic electrophiles. Indeed, when 2-benzylpyridine (4) was reacted with pivalate 5, linear product 7 was obtained in 74% yield and 89% ee (Table 2, entry 1). Unexpectedly, when the reaction was instead conducted with regioisomeric pivalate 6, a mixture of linear and branched products (7 and 8) was formed (entry 2). This is an example of the “memory effect,” in which the regiochemistry of the electrophile influences the regiochemistry of the product.7 When the reaction was performed with 5 in benzene with L2, the linear product was again formed, but with little enantiocontrol (entry 3). However, with 6, the branched product could be obtained in 64% yield and 63% ee8 (entry 4). Thus either regioisomeric product may be obtained exclusively by choosing the appropriate allylic ester and ligand. Table 2. “Memory Effect” Observed with Linear Electrophilesa
entry
ligand
10:11a
yield (%)b
drc
ee (%)d
1 2 3
(S,S)- + (R,R)-L1 (S,S)-L1 (R,R)-L1
1:19 1:1 1:1
97 93 99
9:1 9:1 9:1
+90 -91
a Determined by 1H NMR of the product mixture. b Combined isolated yield of both regioisomers. c Determined by 1H NMR of the crude reaction mixture. d Determined by chiral HPLC.
In summary, we have reported a new method for the highly regio-, diastereo-, and enantioselective allylic alkylation of 2-substituted pyridines. Investigations of the reaction mechanism, the role of lithium aggregates, and applications of this strategy to other nucleophilic classes are ongoing. Acknowledgment. We thank the National Science Foundation and the National Institutes of Health (GM13598) for supporting our programs and Johnson Matthey for palladium salts. Dr. Victor G. Young, Jr. (X-ray Crystallographic Laboratory, University of Minnesota) is gratefully acknowledged for XRD analysis. Note Added after ASAP Publication. A word was inadvertently omitted from the title in the version published ASAP July 31, 2009. The corrected version was published August 7, 2009.
entry
substrate
ligand
solvent
7:8b
yield (%)c
ee (%)d
1 2
5 6
L1 L1
dioxane dioxane
>19:1 1:1.6
74 71
3 4
5 6
L2 L2
PhH PhH
>19:1
